Major depressive disorder (MDD) is a leading cause of disability in the world. Treatment-Resistant Depression (TRD) causes the majority of MDD's disability. Strikingly, 50% of individuals with MDD will fail to remit with two adequate trials of antidepressant medications, thus suffering TRD. In a currently funded R01 project now in its second year, we are conducting a randomized, controlled trial of Mindfulness-Based Cognitive Therapy (MBCT) for the TRD population. MBCT is a group-based, 8-week intervention that uses mindfulness meditation as its core therapeutic ingredient. It teaches people to have a different relationship to depressive thoughts and feelings. This study uses the Health-Enhancement Program (HEP) as a comparator. HEP features physical functioning, nutrition, and music therapy. The study design involves enrollment of 124 patients with MDD who have failed two or more adequate antidepressant trials documented with the Antidepressant Treatment History Form software. Patients are then randomly assigned to one of two groups: MBCT+TAU or HEP+TAU. The overall aim of this study is to test the hypothesis that MBCT+TAU is more effective than HEP+TAU in reducing depressive symptoms and enhancing remission and response rates using the Hamilton Rating Scale for Depression over a period of 8 weeks. In the currently proposed revision to the parent R01 study, we are responding to NIH calls for increased biological understanding of therapeutic interventions. We propose to enroll 80 participants from the R01 to receive fMRI assessments immediately before and after the 8-week MBCT+TAU or HEP+TAU interventions. We propose to implement both emotion regulation (affect labeling) and emotional interference during executive control (emotional working memory) tasks during fMRI scanning to probe the ventral affective processing and dorsal executive control systems before and after the eight weeks of MBCT or HEP. We hypothesize that MBCT+TAU participants will demonstrate greater increases in the dorsolateral prefrontal cortex and greater decreases in activation in the ventrolateral prefrontal cortex and amygdala over the course of treatment, compared to the HEP+TAU participants. Because MBCT focuses on attentional training, we believe it is unique compared to other forms of psychotherapy in directly activating these emotion regulation systems. There is emerging evidence that mindfulness is associated with enhanced activation of components within each of these systems. The results of this study will have clear public health benefits both in terms of identifying an effective treatment for TRD, but also, in elucidating the neural mechanisms associated with MBCT. This may allow for refinement of treatment and enhanced patient selection. PUBLIC HEALTH RELEVANCE: Major depressive disorder (MDD) is a leading cause of disability in the world and the number one cause in North America. Treatment-Resistant Depression (TRD) causes the majority of MDD's disability. Strikingly, 50% of individuals with MDD will fail to remit with two adequate trials of antidepressant medications, thus suffering TRD. Current pharmacological and psychotherapeutic treatment strategies for TRD are limited in effectiveness so new techniques are needed. This grant is a randomized, controlled trial of Mindfulness-Based Cognitive Therapy (MBCT) for the TRD population. If MBCT is shown to be efficacious in this study, it will be of major public health significance. It may lessen disability, decrease morbidity, decrease medical comorbidity and reduce personal suffering in a cost effective intervention. The second phase of this study investigates the fMRI neural patterns of response to MBCT which may help refine its efficacy and lead to better predictions of who may benefit the most from the treatment.